Kidney is a urinary organ of vertebrate animals and comprises a pair of left and right ones at the back of somatic cavity. Renal artery comes in from the concave at the inner side of its center called hilum of kidney and renal vein and ureter comes out therefrom. An inner part of parenchyma of the kidney consists of cortex and medulla. Medulla comprises ten and several complexes and the front end thereof forms nipple. In the cortex, glomerulus is present. The glomerulus is a spherical block of capillaries having a diameter of about 200 μm and carries out filtration of blood. A functional unit of the kidney is called nephron and about one million nephrons are present in one kidney. The nephron comprises glomerulus, capsule of Bowman covering that and proximal convoluted tubule, loop of Henle and distal tubule connecting thereto. The nephron joins a collecting tubule and the collecting tubule opens to renal pelvis at papillary tube via Belluni tube. Urine filtered by the glomerulus is subjected to re-absorption and secretion when passing through the urinary tubule whereupon the final urine is formed. As a result of formation of urine as such, the kidney maintains the homeostasis of internal environment of living body such as 1) excretion of water, 2) excretion of final products of metabolism, particularly nitrogen-containing components, 3) excretion of electrolytes, 4) excretion of heterogeneous substances to body, 5) adjustment of osmotic pressure of blood, volume of body fluid, equilibrium between acid and base, etc. Further, the kidney is an organ which participates in adjustment of blood pressure by way of production and secretion of renin and prostaglandin and also in production of erythrocytes in bone marrow by way of production of erythropoietin.
Generally, kidney diseases are roughly classified into glomerular disease where disorder is noted in glomerulus and tubular diseases where disorder is noted in urinary tubule. Although no effective drug is available at present for the treatment of kidney diseases, there have been clinically used steroids, immunosuppressants, anti-platelet agents/anticoagulants, prostaglandin preparations, hypotensive/diuretic preparations, etc. Among them, steroids are particularly commonly used, but on the other hand, severe side effects such as cataract and osteoporosis by the use of steroids have been known. In nephritis to which drugs are not applicable, treatment for the purpose of retarding the transfer to chronic renal failure has been done by, for example, means of dietary restriction (low-protein meals). Anyway, when nephritis becomes chronic and progressive, treatment is difficult and, finally, renal failure is resulted whereby dialysis of blood has to be forcibly applied. Dialysis of blood causes much burden to patients both economically and physically and, as the dialyzing period becomes long, may result in a problem such as expression of complication with other diseases (such as cerebral and cardiac diseases). In addition, from a social view, enormous medical cost for dialysis is needed and, therefore, there has been a brisk demand for the development of new and useful drugs which inhibit or retard the transfer to dialysis.
PAR (protease-activated receptor)—2 is a protease receptor which is a member of a family of G protein conjugation type receptor of a seven-transmembrane type.
With regard to PAR, four types—PAR-1, PAR-2, PAR-3 and PAR-4— have been cloned up to now and they belong to a receptor family mediating the action of serine proteases such as thrombin and trypsin on various kinds of cells. With regard to each of PAR-1, PAR-3 and PAR-4, its function has been clarified as a receptor relating to platelet coagulation by thrombin while, with regard to PAR-2, although it has many common points with other PARs in terms of structure and activation mechanism, it is different from other PARs in terms of function such as that it is not activated by thrombin and it is activated by trypsin or tryptase.
In those PARs, specific site of amino acid sequence of N-terminal of PAR molecule is cleaved by the action of thrombin or protease and the newly exposed cleaved terminal bonds to the bonding site of the receptor per se whereupon the receptor is activated. Outline of the amino acid sequence which activates the receptor at the cleaved site is shown by means of a one-letter expression of amino acid.
PAR-1SFLLRN-NH2(human)PAR-2SLIGKV-NH2(human)SLIGRL-NH2(mouse)PAR-3(none)PAR-4GYPGQV(human)GYPGKF(mouse)
PAR-1, PAR-2 and PAR-4 are able to be non-enzymatically activated by exogenous peptide having an amino acid sequence of the cleaved site while PAR-3 is unable to be activated by such an exogenous peptide. In recent studies, it was proved that mouse PAR-3 per se is not activated but is a co-factor for PAR-4 which is able to function only in the co-presence with PAR-4 (Nature, 404, 609-613, 2000).
PAR-2 was cloned in 1994 by Nystedt, et al. (Proc. Natl. Acad. Sci. USA, 91, 9208-9212, 1994) and has been known to be activated by synthetic peptide having the same sequence as the above PAR-2 ligand, trans-cinnamoyl-LIGRLO-NH2 which is a derivative thereof (Br. J. Pharmacol., 123, 1434-1440, 1998), trypsin, tryptase, tissue factor/VIIa factor, Xa factor, acrosin which is a kind of sperm protease and trypsin-like serine protease identified from brain of rat (Pharmacological Rev., 53, 245-282, 2001).
Physiological significance of activation of PAR-2 and its participation in pathology have been investigated in various kinds of cells, tissues and animal models and it has been reported that rolling and adhesion of leukocytes, infusion of neutrophils, secretion of inflammatory cytokines and leakage of plasma protein are induced and that onset and worsening of arteriosclerosis, dermatitis and acute inflammation are induced in experimental systems of in vitro and in vivo (Circulation, 99, 2590-2597, 1999; Thromb. Haemost., 81, 808-814, 1999; J. Neurochem., 69, 1890-1896, 1997; Br. J. Pharmacol., 125, 419-422, 1998; Br. J. Pharmacol., 127, 1083-1090, 1999; Eur. J. Pharmacol., 328, 89-97, 1997; Nat. Med., 6, 151-158, 2000; J. Immunol., 163, 5064-5069, 1999; J. Immunol., 159, 6216-6225, 1997; J. Immunol., 161, 1939-1946, 1998; Immunology, 94, 356-362, 1998; J. Biol. Chem. 276, 31657-31666, 2001; J. Immunol., 165, 6504-6510, 2000; Jpn. J. Pharmacol., 88, 77-84, 2002). All these reports show that activation of PAR-2 induces inflammation and worsens it. As such, it has not been expected at all that activation of PAR-2 tends to suppress a certain type of inflammation. It has been also unknown at all that activation of PAR-2 is effective for prevention and treatment of kidney diseases.